Methods, Systems And Compositions For The Novel Use of Enterobactin to Treat Iron Deficiency And Related Anemia And Promote Red Blood Cell Production

Abstract

In one embodiment, the invention relates to the use of ferric enterobactin (Fe Ent), and/or Fe-Ent analogs as a therapeutic agent to treat iron deficiency and anemia. In a preferred embodiment, Fe-Ent and/or Fe-Ent analogs may be delivered to a host organism, such as a human subject to treat an iron-related disease condition or other anemia. In alternative embodiments, delivered to a host organism, such as a human subject to promote production or red blood cells. In such an embodiment, Ent and/or Ent analogs may be delivered to a human subject in need thereof through a pharmaceutical composition or through a genetically engineered bacteria, such as a probiotic organism configured to express Ent.

What is claimed is: 
     
         1 . A method of treating iron-deficiency comprising administering a therapeutically effective amount of ferric enterobactin (Fe-Ent), or an Fe-Ent analog, or a pharmaceutically acceptable to salt in a subject in need thereof 
     
     
         2 . The method of  claim 1 , wherein said Fe-Ent analog is selected from the group consisting of: TRENCAM, SERSAM, SER(3M)SAM, TRENSAM, and TREN(3M)SAM, wherein said Fe-Ent analogs may be complexed with iron. 
     
     
         3 . The method of  claim 1 , wherein said therapeutically effective amount of Fe-Ent, or said Fe-Ent analog is isolated. 
     
     
         4 . The method of  claim 1 , wherein said Fe-Ent, or Fe-Ent analog is combined with a pharmaceutically acceptable carrier. 
     
     
         5 . The method of  claim 4 , wherein said pharmaceutically acceptable carrier comprises a nutritional supplement. 
     
     
         6 . The method of  claim 5 , wherein said nutritional supplement comprises a probiotic bacterium configured to express a heterologous nucleotide, operably linked to a promotor, encoding one or more genes for the biosynthesis of Ent. 
     
     
         7 . The method of  claim 1 , wherein said iron-deficiency comprises iron-deficiency anemia, or anemia caused by dysregulation in the DMT1 iron uptake system of said subject, anemia caused by low erythrocyte counts. 
     
     
         8 . The method of  claim 7 , wherein said subject in need thereof comprises a human subject. 
     
     
         9 . A method of treating iron-deficiency or anemia comprising administering a therapeutically effective amount of a genetically modified probiotic bacteria expressing a heterologous nucleotide, operably linked to a promotor, encoding one or more genes for the biosynthesis of enterobactin (Ent) that may be complexed with iron to form Fe-Ent. 
     
     
         10 . The method of  claim 9 , wherein said probiotic bacteria comprises an Enterobacter probiotic bacterium. 
     
     
         11 . The method of  claim 9 , wherein said heterologous nucleotide comprises a heterologous nucleotide encoding one or more of the genes selected from the group consisting of: entA entB, entC, entD, entE, and entF. 
     
     
         12 . The method of  claim 9 , wherein said heterologous nucleotide comprises a heterologous nucleotide sequence encoding one or more of the amino acid sequences selected from the group consisting of: SEQ ID NO's. 1-6. 
     
     
         13 . The method of  claim 9 , wherein said a subject in need thereof is a human subject. 
     
     
         14 . The method of  claim 13 , wherein said iron-deficiency comprises iron-deficiency anemia, or anemia caused by dysregulation in the DMT1 iron uptake system of said subject. 
     
     
         15 . A method comprising:
 administering a therapeutically effective amount of ferric enterobactin (Fe-Ent), Fe-Ent analog, or a or a pharmaceutically acceptable salt to a subject in need thereof and exhibits one or more effects in said subject:
 promotes mitochondrial iron uptake in said subject by the binding of said Fe-Ent, Fe-Ent analog, or a pharmaceutically acceptable salt thereof to ATP synthase α-subunit; 
 treats symptoms of iron-deficiency, and optionally iron-deficiency anemia in said subject; 
 treats symptoms of anemia caused by dysregulation in the DMT1 iron uptake system of said subject; and 
 promotes the production of erythrocytes in said subject. 
   
     
     
         16 . The method of  claim 15 , wherein said Fe-Ent analog is selected from the group consisting of: TRENCAM, SERSAM, SER(3M)SAM, TRENSAM, and TREN(3M)SAM, wherein said Fe-Ent analogs may be complexed with iron. 
     
     
         17 . A method of  claim 15 , wherein said therapeutically effective amount of Fe-Ent, or said Fe-Ent analog is isolated. 
     
     
         18 . A method of  claim 15 , wherein said step of administering a therapeutically effective amount of Fe-Ent, or a Fe-Ent analog comprises administering a nutritional supplement having, or being configured to biosynthesize, a therapeutically effective amount of Fe-Ent that may be complexed with iron to form Fe-Ent. 
     
     
         19 . A method of  claim 17 , wherein said nutritional supplement comprises a probiotic bacterium configured to express a heterologous nucleotide, operably linked to a promotor, encoding one or more of the genes selected from the group consisting of: entA entB, entC, entD, entE, and entF.